azacosterol and Disease-Models--Animal

Previous spin-label and electromyographic experiments with rats fed 20,25-diazacholesterol, an inhibitor of the biosynthetic conversion of desmosterol to cholesterol, demonstrated an increased erythrocyte membrane fluidity and myotonia, a prolonged muscle contraction upon stimulation. The current studies with rats showed normal erythrocyte fluidity in animals fed 20,25-diazacholesterol but maintained on a high-cholesterol diet and no myotonia. Studies of model membrane systems composed of phospholipid vesicles containing desmosterol, cholesterol, or both demonstrated that desmosterol increased membrane lipid fluidity relative to cholesterol, suggesting that in 20,25-diazacholesterol-induced myotonia, in which desmosterol accounts for 85% of the plasma sterol, the increased membrane fluidity previously observed in erythrocytes and sarcolemma in this animal model of human congenital myotonia may be due to desmosterol.

Topics: Animals; Azacosterol; Cholesterol, Dietary; Desmosterol; Disease Models, Animal; Erythrocyte Membrane; Liposomes; Male; Membrane Fluidity; Myotonia; Rats; Rats, Inbred Strains

Several drugs that interfere with sterol metabolism have been associated with hyperkeratosis in man. We found that 20,25-diazacholesterol (30 to 60 mg/kg/day), administered to hairless mice that were otherwise given normal laboratory chow and water ad libitum, consistently produced ichthyosis after 6 to 9 weeks, an effect that was reversible with removal of drug or with coadministration of a high cholesterol diet. Scaling was most pronounced over the tail, but some stratum corneum retention was noted over the entire skin surface. As measured in frozen sections, stratum corneum thickness was three to 10 times thicker in treated animals than in either controls or revertants. Oil red O-stained frozen sections and freeze fracture replicas revealed decreased stratum corneum membrane lipids in the diazacholesterol-treated animals, but this finding was not specific, since a similar deficit was found in control and revertant tail stratum corneum but not in the stratum corneum from other sites. Stratum corneum lipid extracts revealed reduced total free sterols, reduced cholesterol, accumulation of several normally absent sterol precursors, and increased glycosphingolipids on thin-layer chromatography and high pressure liquid chromatography. In summary, we describe a syndrome of drug-induced ichthyosis in hairless mice that parallels the drug-induced syndrome in man. This syndrome is reversible and accompanied by distinctive abnormalities in cutaneous sterol metabolism. The diazacholesterol model may further our understanding of the pathogenesis of human keratinizing disorders and may provide a valuable analogue for testing new forms of therapy, such as retinoids, for scaling dermatoses.

Topics: Animals; Azacosterol; Cholesterol; Disease Models, Animal; Freeze Fracturing; Glycosphingolipids; Ichthyosis; Lipids; Male; Mice; Mice, Hairless; Skin; Tail

Topics: Animals; Azacosterol; Disease Models, Animal; Electromyography; Male; Mitochondria, Muscle; Motor Endplate; Myotonic Dystrophy; Oculomotor Muscles; Rats